Title:  Intracellular pharmaceutical targeting

United States Patent:  6,358,697

Assignee:  Children's Hospital Medical Center (Cincinnati, OH)

Filed:  April 21, 1999

A method and composition to target compounds into cells such as eosinophils. A ligand for a CCR-3 eosinophil surface receptor is provided under conditions to bind to the receptor and cause internalization of the ligand-CCR-3 complex. A compound, such as a drug in an active or inactive form, may be bound to the ligand and delivered to an intracellular site of the cell where it may subsequently become activated. The methods and compositions may be used to treat a variety of eosinophil-mediated disorders, for example, allergies.

SUMMARY OF THE INVENTION

The invention is directed to a method for intracellular targeting. A ligand for a cellular CCR-3 surface receptor is provided under conditions to form a ligand-receptor complex, and the ligand-receptor complex is internalized into the cell. The internalized complex may alter a cellular function, such as cell proliferation, cell viability, chemotaxis, activation, trafficking, and/or preventing subsequent ligand binding. The ligand may have a compound bound to it, such as a toxin, a drug, an enzyme and/or a radionuclide, and the compound may be activated intracellularly. The compound may be bound to the ligand in a variety of ways, such as covalently or noncovalently, or a protein compound may be generated as a fusion protein with said ligand. The ligand may be eotaxin, eotaxin-2, RANTES, monocyte chemoattractant protein (MCP)-2, MCP-3 and/or MCP-4. The cell may be an eosinophil, a basophil, a lymphocyte and/or a microglial cell.

The invention is also directed to a composition for treating an eosinophil-mediated disorder. The composition is a ligand for a CCR-3 eosinophil receptor containing a compound such as a leukotriene inhibitor and/or an apoptosis inducer in a pharmaceutically acceptable formulation. The composition may be used to treat eosinophil-mediated disorders such as allergies, asthma, eczema, eosinophilic cardiomyopathy, eosinophilic gastroenteritis, hypereosinophilic syndrome, graft versus host disease, chronic fibrosis, a parasitic inflammatory disorder, drug reaction, eosinophilic pneumonias, episodic angioedema with eosinophilia, inflammatory bowel disease, eosinophilic leukemia and/or food enteropathy. The compound may be a prodrug that is activated upon internalization into the eosinophil.

The invention is further directed to a method to prevent eosinophilia by providing a ligand for a CCR-3 receptor on an eosinophil under conditions to form a ligand-receptor complex and internalizing the complex into an eosinophil. The method may have a compound bound to the ligand, such as a toxin, a drug, an enzyme, a leukotriene inhibitor, and/or an apoptosis inducer, and may be activated upon internalization into the eosinophil.

The invention is still further directed to a method to treat or protect against a human immunodeficiency virus (HIV). A ligand for a CCR-3 cell surface receptor is provided in a pharmaceutically acceptable formulation and under conditions to form a ligand-CCR-3 complex. HIV binding to the CCR-3 is prevented by internalizing the ligand-CCR-3 complex.

The invention is additionally directed to a method for down-regulating a CCR-3 cell surface receptor. A ligand for the receptor is provided under ligand-binding conditions, the ligand is bound to the receptor and the ligand and receptor are internalized into the cell. The ligand may be a chemokine, a chemokine analog, a small molecule antagonist and/or a small molecule agonist and may have a compound bound to the ligand.

One advantage of the invention includes the ability to prevent systemic drug toxicity by administering an drug that is activated intracellularly.

Claim 1 of 25 Claims

What is claimed is:

1. A method of intracellular targeting comprising providing a compound bound to a ligand for a CCR-3 surface receptor on a cell under conditions to form a ligand receptor complex and internalizing said complex into the cell.

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